Thesis

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  • (2022) Young, Clara
    Thesis
    A breakdown in B cell self-tolerance can lead to antibody-mediated autoimmune disease. This thesis aims to explore how B cell tolerance can be broken in two distinct, but complementary projects within the context of the Goodnow somatic mutation hypothesis. In both scenarios, B cells that escape self-tolerance and generate autoantibodies are referred to as “rogue” B cells. First, this thesis aimed to elucidate the precise steps undertaken by expanded rogue B cell clones in patients with chronic Hepatitis C virus (HCV)-associated cryoglobulinemic vasculitis, an autoimmune disease characterised by the production of a rheumatoid factor cryoglobulin autoantibody. The rogue B cell clones in the HCV cryoglobulinemic vasculitis patients were confirmed to be the source of the autoantibody. The rogue B cell clone precursor antibodies failed to bind the HCV envelope glycoprotein E2, yet bound multimerised self-antigen IgG relative to membrane IgM density. These findings disfavour a molecular mimicry hypothesis, and instead indicate IgG immune complexes may be sufficient to drive recruitment of the rogue B cell clone precursors. Finally, the rogue B cells clones were found to carry somatic lymphoma-associated, non-immunoglobulin gene mutations and chromosomal aberrations, predicted to cause hyperactivation of the NF-kB signalling pathway and escape of B cell tolerance. This finding provides additional evidence in support of the Goodnow somatic mutation hypothesis. Second, this thesis examined rogue germinal centre (GC) B cells that arise in the absence of the receptor FAS. Rogue GC B cells loose specificity for the foreign antigen and incidentally generate autoantibodies. However, the accumulation of rogue GC B cells cannot be explained by our current understanding of affinity-based selection in the GC. This work revealed rogue GC B cells, unlike “conventional” GC B cells undergoing affinity maturation to the foreign antigen, can be identified by low expression of CD21 and high expression of B220 (CD21loB220hi). Moreover, rogue GC B cells were found to be rapidly entering cell cycle, enriched for a dark zone phenotype and T-cell dependent, reminiscent of positively selected GC B cells. Thus, rogue GC B cells typically removed by FAS, likely persist in the competitive GC microenvironment despite their loss of BCR specificity to foreign antigen, because they retain the capacity to undergo T-cell dependent positive GC selection.

  • (2021) Short, Katherine
    Thesis
    Children experiencing social and environmental adversity are at greater risk of language difficulties and the related long-term educational and social life challenges. Early years interventions such as home visiting are designed for this vulnerable group and target a range of factors that may influence language outcomes. Many fixed, less modifiable and more modifiable risk and protective factors are known to influence language development. However, it is not clear which factors influence language outcomes in children experiencing adversity nor how these factors combine, especially in the context of intervention. This thesis used qualitative and quantitative methods to investigate the influence of: i) 16 different risk and protective factors and ii) a home visiting intervention on the language outcomes of two groups of children experiencing adversity (n=234). Data were extracted from three longitudinal studies: the Gudaga birth cohort, the Bulundidi Gudaga study and the Maternal Early Childhood Sustained Home-visiting randomised control trial. Several factors influenced language outcomes in urban Aboriginal children. Receptive vocabulary at 3 years was predicted by the child’s gender, non-verbal cognition, number of children in the home and maternal education, and at 4 years by mothers’ emotional well-being, home visiting intervention and daily book reading. In a low socioeconomic status culturally and linguistically diverse cohort, multiple combinations of cumulative risk and protective factors resulted in ‘good’ and ‘poor’ language development, with and without home visiting intervention. While all factors explored, including toddler development, maternal education, early childhood education, number of children in the home and language spoken, impacted on children’s language outcomes, the pervasive influence of two modifiable factors – maternal psychological resources and responsivity – were key. This thesis details the impact of varying combinations of risk and protective factors and a home visiting intervention on language development in two cohorts of children experiencing adversity. Children’s environments made a difference to their learning. Maternal psychological resources, responsivity, home visiting, book reading, the number of children at home and early childhood education were all important, in varied combinations, in children’s language outcomes. These findings have the potential to inform more precise home visiting early interventions so they can respond to the individual characteristics of children and families.

  • (2022) Zulkifli, Muhammad Yazid Bin
    Thesis
    Zinc-azole-based metal organic frameworks (MOFs) have been demonstrated to exist in a wide variety of structural states, with applications in different fields such as gas separation. In this dissertation, we explore the phase control and dynamics of zinc-azolebased MOFs in crystalline, liquid, and glassy states. We first study ZIF-7 phase control using mechanochemical synthesis. Ammonium nitrate was found to be a good catalyst in mechanochemical ZIF formation, with the usage of DMF and H2O favouring ZIF-7-I and ZIF-7-III formation, respectively. New phases of ZIF-7 variations not accessible using the solvothermal method were also obtained mechanochemically indicating the possibility of a new mechanochemical synthesis route. The mechanochemical ZIF-7 mixed matrix membrane (MMM) demonstrates good CO2- based selectivity improvements. Next, we demonstrate the formation of a new meltable zinc-azole framework (ZnCP) with liquid crystal behaviour by the addition of orthophosphate. ZnCP was able to melt at a low temperature while retaining and orienting its crystallinity into transparent liquid, thus showing promising use in optical-based applications. This material can also be obtained using a top-down approach by adding phosphoric acid to ZIF-7. Controlling phosphoric acid incorporation results in different melted ZnCP particle ratios, which was explored as a gas separation membrane. We then explore the effect of silver (Ag) composite presence on the thermal dynamics of another zinc-azole framework (ZIF-62). The benzimidazole amount within the Ag-doped ZIF-62 structure affects its thermal conversion, forming either Ag-doped ZIF-zni or Agdoped ZIF glass. The thermal dynamics of Ag-doped structures were explored using both in-situ (thermal) and ex-situ techniques. Both Ag-doped phases were demonstrated to have good MMM separation improvements for CO2 and light hydrocarbon, indicating the accessibility of the silver composite. Lastly, a quick demonstration of new methods (dip and spin coating) to process ZIF-62 and ZIF-62 composite successfully forms continuous particle dispersion, allowing the formation of a continuous glass layer. Different compositions such as sandwiched structure and layer by layer were explored, with advantages outlined. The novelty of this dissertation lies within the exploration of new synthetic methods and thermal dynamics to form structurally diverse zinc-azole MOFs which will be beneficial in the understanding of phase transformations in MOFs

  • (2022) Yakubov, Vladislav
    Thesis
    Laser powder bed fusion is a manufacturing process where parts are fabricated layer-by-layer from computer model data. This additive process contrasts with traditional methods such as casting or powder metallurgy, which require a mould to be created and impart geometric part design constraints. Since parts are fabricated directly from a computer model with little or no part-specific preparation, laser powder bed fusion is ideal for rapid prototyping, one-off part fabrication, and individually customized implants for medical industry. Nevertheless, a limited number of alloys can be laser powder bed fusion fabricated without defects due to rapid solidification and high thermal gradient. Furthermore, Al-Si system is currently popular for laser powder bed fusion since it offers defect-free fabrication and rapid solidification-induced solid solution strengthening. However, Al-Si system is not thermally stable. Elevated temperature exposure initiates Si diffusion out of Al matrix, resulting in coarse Si agglomerate formation and mechanical properties reduction. For top value applications in automotive and aerospace industries, it is necessary to explore alloy systems that result in not only defect free fabrication, but also formation of a coarsening resistant microstructure. Previous research on heat tolerant Al alloys fabricated via casting determined that the Al-Ce and Al-Ce-Si system results in formation of coarsening resistant intermetallic precipitates. Despite these alloys exhibiting excellent strength retention at elevated temperatures, room temperature ductility was low, and this appeared to be due to coarse needle-like precipitate morphology formed due to low cooling rate during casting. This research investigates application of AlSi10Mg in-situ alloyed with 4 wt.% Ce and Al6061 in-situ alloyed with 1-7 wt.% Ce for laser powder bed fusion. Defect formation mechanisms are investigated, microstructure development is evaluated, mechanical properties are characterized, and coarsening resistance is studied. It is established that Ce addition is effective in forming a coarsening resistant microstructure. Furthermore, laser powder bed fusion results in homogeneous distribution of nano-scale precipitates, resulting in high ductility. Findings in this research increase understanding of laser powder bed fusion and rapid solidification of Al-Ce-Si alloy system and are valuable for propagation of heat-tolerant alloys suitable for additive manufacturing.

  • (2022) MacGibbon, James
    Thesis
    HIV pre-exposure prophylaxis (PrEP) is a recent, yet significant, development in HIV prevention. This mixed-methods research followed PrEP’s introduction in Australia, and examined how gay, bisexual and queer (GBQ) men in relationships have adapted to and incorporated PrEP in their sex practices, relationships, and everyday lives. As PrEP raises the prospect of having condomless sex both within and outside primary relationships without risking HIV infection, this research revisited the concept of negotiated safety (Kippax et al., 1997) to explore how HIV-negative GBQ men practice and negotiate safe sex in the era of biomedical HIV prevention. Quantitative data were collected in two national cross-sectional survey projects, The Gay Community Periodic Surveys (GCPS; 2013–2018) and the PrEPARE Project (2013–2021). The GCPS analysis showed a rapid shift away from relationship agreements in which condomless sex is only sanctioned between regular partners. The PrEPARE Project analysis found that men in relationships who used PrEP were more likely to have spoken and non-monogamous agreements, and to have partners that also used PrEP, compared to men in relationships who did not use PrEP. Qualitative data were generated using semi-structured, in-depth interviews conducted between January and August 2019 with 26 GBQ men in Sydney, Melbourne and Perth. Thematic analysis of these data identified new shared meanings and social practices that were enabled or mediated by PrEP, with an analytic focus on complexity, situatedness, contingency and relationality. Participant accounts illustrated diverse sexual practices and views about risk, but most participants adopted PrEP due to perceived HIV risk from casual sex rather than sex with their primary partners. PrEP complicated views about what counted as ‘safe sex’ and revealed changing understandings and practices of intimacy, pleasure, trust and risk. There was, however, an enduring narrative of individual responsibility to practice effective HIV prevention. Participants diverged in how they discussed and disclosed sexual practices with their primary and casual partners, revealing tensions about what disclosures were believed to be necessary or expected. Together, these quantitative and qualitative data collected as PrEP use became more common refocus attention on the practicality and complexity of relationship agreements among GBQ men.